Acetals and ketals of 16,17-dihydroxy steroids of the pregnene series



United States Patent Ofi ice 3,134,770 Patented May 26, 1964 3,134,770 ACETALS AND KETALS F 16,17-DIHYDROXY STEROIDS OF THE PREGNENE SERIES Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Nov. 7, 1961, Ser. No. 150,623

14 Claims. (Cl. 260-21955) wherein R is in either the alpha or beta position and represents hydrogen, halogen (preferably chloro and fluoro), or lower alkyl; R is hydrogen or the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms; P is hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q is a monocyclic cycloalkyl or monocyclic heterocyclic radical. The final products of this invention are physiologicallyactive substances which posses progestational activity when administered both in the form of tablets and as a solution or suspension and hence can be used in lieu of known progestational agents, such as progesterone, in the treatment of habitual abortion. For thispurpose, they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. The compounds of this invention can also be administered perorally in the form of tablets.

In accordance with one process of this invention, the compounds of this invention can be prepared by reacting a compound of the formula wherein R (in either the alpha or beta position), P and Q are as hereinbefore defined, with a lower alkanediol (e.g., ethylene glycol, propylene glycol) to yield the new 3-ketals of this invention of the formula wherein R, P and Q are as hereinbefore defined and A is a lower alkylene radical, preferably ethylene. The reaction is preferably conducted in an organic solvent for the steroid reactant at an elevated temperature, preferably the reflux temperature of the solvent, in the presence of an acid catalyst, such as p-toluenesulfonic acid.

The resulting 3-ketal is then reduced, as by treatment with lithium aluminum hydride or a borohydride (e.g., sodium borohydride and lithium borohydride) to yield the new 3-ketal-20B-hydroxy intermediates of this invention of the formula wherein R, P, Q and A are as hereinbefore defined. This reaction is preferably carried out at an elevated temperature, such as the reflux temperature of the solvent used to dissolve the steroid reactant.

The 3-ketal-20fl-hydroxy compounds are then hydrolized, as by treatment with a dilute acid, such as a dilute mineral acid as exemplified by dilute sulfuric acid, to yield the final products of this invention wherein R is in the alpha position.

The final products of this invention can also be prepared from the same starting materials by a second process of this invention, wherein the starting steroid is reduced by treatment with lithium aluminum hydride or a borohydride Without protection of the 3-keto group. In this event both the 3-keto and the 20-keto groups are reduced, yielding new 3,8,20fi-dihydroxy intermediates of this invention of the formula 9 HOCH p I --o P These intermediates are then selectively oxidized by treatment with manganese dioxide to yield the final 3- keto-fl-hydroxy compounds of this invention.

Among the suitable initial steriod reactants may be mentioned the 16,17-acetals and ketals of each of the following steroids with one of the aldehydes or ketones listed hereinafter: 1604,170. dihydroxyprogesterone; 6- halo 16a,17a-dihydroxyprogesterones, such as 60L-flll010- l6oz,l7oc dihydroxyprogesterone, 6,B-fluoro-l6u,l7a-dihydroxyprogesterone, 6oz chloro 16a,17a-dihydroxy progesterone, 65 chloro l6u,17u-dihydroxyprogesterone, 6a bromo l6oz,l7zx dihydroxyprogesterone and 6,3 bromo 16a,17a-dihydroxyprogesterone; and 6 (lower alkyl) 16a,17ot dihydroxyprogesterones, such as 604 methyl l6u,17a dihydroxyprogesterone, 6,8 methyl 1604,1711: dihydroxyprogesterone and 6c:- ethyl-l6al7a-dihydroxyprogesterone.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutyl-ketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone, cyclohexanone, suberone, and cyclodecanone; cycloalkyl (lower alkanals), such as cyclopropylcarboxaldehyde, cyclobutylcarboxaldehyde, cyclopentylcarboxaldehyde cyclohexylcarboxaldehyde, cy cloheptylcarboxaldehyde, cyclooctylcarboxaldehyde, cyclopropylacetaldehyde, cyclobutylacetaldehyde, cyclopentylacetaldehyde, cyclohexylacetaldehyde, {3 cyclopentylpropionaldehyde, 'y cyclohexylbutyraldehyde, and 3 cyclopropylcarproaldehyde; cycloalkyl(lower alkanones), such as cyclopropyl methyl ketone, cyclobutyl ethyl ketone, cyclopentyl propyl ketone, cyclopentyl methyl methyl ketone, cyclohexylmethyl ethyl ketone, cyclopentylethyl ethyl ketone, cyclopropylpropyl methyl ketone, cyclohexyl n-pentyl ketone, cyclohexyl methyl ketone, and cyclooctyl methyl ketone; dicycloalkyl ketones, such as dicyclopropyl ketone, dicyclobutyl ketone, dicyclopentyl ketone, dicyclohexyl ketone, cyclopentyl cyclohexyl ketone, cyclopropylmethyl cyclopropyl ketone, 2-cyclobutylethyl cyclopropyl ketone, 3-cyclopentylmethyl cyclopentyl ketone, 5-cyclohexylhexyl cyclohexyl ketone, di(cyclopentylmethyl)ketone, cyclohexylmethyl cyclopentyl ketone, and di(4-cyclohexylpentyl)ketone; cycloalkyl monocyclic aromatic ketones, such as cyclopropyl phenyl ketone, cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxyphenyl ketone, cyclohexyl m-tolyl ketone, cyclopropyl p-ethylphenyl ketone cyclopropyl p-nitrophenyl ketone, and cyclohexyl p-acetamidophenyl ketone; cycloalkyl(lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic (lower alkyl) ketones, such as cyclopentyl benzyl ketone, cyclohexyl phenethyl ketone, and cyclobutyl benzyl ketone; cycloalkyl(lower alkyl) monocyclic aromatic (lower alkyl) ketones, such as cyclopentylmethyl benzyl ketones; cycloalkyl monocyclic heterocyclic ketones, such as cyclopentyl 2-furyl ketone, cyclohexyl Z-thienyl ketone, and cyclopropyl 2-pyridinyl ketone; cycloalkyl (lower alkyl) monocyclic heterocyclic ketones, such as cyclopentylmethyl 2-piperidinyl ketone, cyclohexylethyl 2-morpholinyl ketone and cyclopropyl 2-thienyl ketone; cycloalkyl monocyclic heterocyclic (lower alkyl) ketones, such as cyclopentyl thenyl ketone, cyclohexyl furfuryl ketone and cyclopropyl 2-piperidinylmethyl ketone; halo-lower alkanals, such as chloral hydrate, trifiuoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1,1,1-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fiuorobenzaldehyde), lower alkoxybenzaldehydes (e.g. o anisaldehyde), di(lower alkoxy) benzaldheydes (e.g., veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxybenzaldehydes (e.g. resorcyaldehydc), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g., o-p-dimethylbenzaldehyde), nitrobenzaldehydes, acylamidobenzaldehydes (e.g. N- acetylanthranilaldehyde), and cyanobenzaldehydes; monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a phenylpropionaldehyde, fl phenylpropionaldehyde, *y phenylbutyraldehyde, and aromatically-substituted halo lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; monocyclic heterocyclic lower alkanals; monocyclic carbocyclic aromatic ketones, such as acetophenone, 0c,ot,oc trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and pchloropropiophenone), (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone), di-(lower alkoxy)phenyl lower alkyl ketones, hydroxy-phenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone), di(lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone), acylamidophenyl lower alkyl ketones (e.g., acetyl anilines), and cyano phenyl lower alkyl ketones; benzophenone, and mono or bis substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and 1-phenyl-4- pen-tanone, and aromatically substituted derivatives thereof; monocyclic heterocyclic ketones, such as 2-acetylfuran, Z-benzoylfuran, 2-acetyl-thiophene and alloxan; and monocyclic heterocyclic lower alkanones.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 a,] 7oc-D ihy droxy progesterone 160a,] 7'a-A cetonide 3-M0n0ethylene Ketal To a solution of 1 g. of 16a,17a-dihydroxyprogesterone acetonide in 50 ml. of benzene and 10 ml. of ethylene glycol is added 20 mg. of p-toluene-sulfonic acid mono hydrate and the mixture is refluxed for 20 hours using a Dean-Stark phase separator. Sodium bicarbonate solution is added to the cooled mixture which is then washed with water and the benzene phase dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the crude residue from acetone-hexane yields about 625 mg. (56% yield) of l6a,17o-dihydroxyprogesterone 16a,l7oz-&Cet0l1id6 3-monoethylene ketal, M.P. about -195 C. Recrystallization from acetone yields the analytically pure monoketal with the following properties: M.P. about 201-203 C.; [011 +ll.7 (c., 1.2 in chlf.);

A Nuiol max.

no selective UV. absorption.

EXAMPLE 2 16a,]7a-Dihydroxyprogesterone 160a,] 7a-A cetoplzenonide 3-M0n0ethylene Ketal 16,17-acetophenonide 3-ethylene ketal, M.P. about 173- 179 C. Recrystallization from ethanol-methanol gives the analytically pure ketal with the following properties. MP. about 184186 C.; [M 45.0 (0., 1.0 in chlf.)

)\ Elli? 5.83, 12.95 and 1320 .4

no selective UV. absorption.

Analfl-Calcd. for C H O (492): C, 75.58; H, 8.18. Found: C, 75.34; H, 8.36.

Similarly, if propylene glycol is substituted for the ethylene glycol in the procedures of Examples 1 and 2, the corresponding 3-monopropy1ene ketals are formed.

EXAMPLE 3 1611,] 7ot-Ch0ral Derivative of A -Pregnene-16a,17a-Diol- 3,20-Dine S-Ethylene Ketal Following the procedure of Example 1 but substituting an equivalent amount of the 16ot,17ut-Ch10131 derivative of 16a,17a-dihydroxyprogesterone for the 16a,l7a-dihydroxyprogesterone 16,17-acetonide, the 16a,17ot-chloral derivative of A -pregnene-16a,l7ot-diol-3,2O-dione 3-ethylene ketal is obtained.

EXAMPLE 4 16,]7-Dicycl0pr0pyl Ketone Derivative of M-Pregnene- 1611,] 7tx-Diol-3,20-Dione 3-Ethylene Ketal Following the procedure of Example 1 but substituting an equivalent amount of the 16a.,17a-dicyclopropyl ketone derivative of 16a,17ot-dihydroxyprogesterone for the 16a,l7a-dihydroxyprogesterone 16,17-acetonide, the dicyclopropyl ketone derivative of A -pregnene-16a,17otdiol 3-ethylene ketal is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative, heptafiuorobutanal derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaldehyde derivative, the furfural derivative, the benzophenone derivative and the Z-acetylfuran derivative of 16a,l7et-dihydroxyprogesterone, yield the methylisobutyl ketone, the cyclopropyl phenyl ketone, the cyclohexyl methyl ketone, the 1,1,1-trifluoroacetonide, the heptafiuorobutanal, the p-chloroacetophenone, the p-nitroacetophenone, the benzaldehyde, the furfural, the hemephenone and the Z-acetylfuran derivatives of A -pregnene- 16a,17nc-diOl-3,20-di0l1e 3-etl1ylene ketal respectively.

EXAMPLE 5 o-Chloro-M-Pregnene-l 6 00,1 7u-Diol-3,20-Dione 16,17-Acet0nide 3-Ethylene Ketal Following the procedure of Example 1 but substituting an equivalent amount of 6,3-chloro-M-pregnene-l6a,17u diol-3,20-dione 16,17-acet0nide for the l6m,17a-dihydroxyprogesterone 16,17-acetonide, 6-chloro-A -pregnene- 16a.,170t-di01-3,Z0-di0116 16a,17ot-acetonide 3-ethy1ene ketal is obtained.

EXAMPLE 6 6-Chl0r0-A -Pregnene-1 6 u,] 7a-Di0l-3 ,2 0-Di0ne 16,1 7-A cetonide 3-Ethylene Ketal Following the procedure of Example 1, but substituting 6ot-chloro-16a,17a-dihydroxyprogesterone 16,17-acetonide for the 16a,17a-dihydroxyprogesterone 16,17-acetonide, 6-chloro-A -pregnene-16a, l7u-diol-3 ,ZO-dione 16,17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 7 6-Flu0r0-M-Pregnene-1 6 oz,] 7a-Di0l-3,20-Di0ne 1 6,1 7 -A cetonide 3 Ethylene Ketal Following the procedure of Example 1, but substituting 6,8-fluoro 16a,17u-dihydroxyprogesterone 16,17-acetonide for the 16a,l7et-dihydroxyprogesterone 16,17-acetonide, 6-fluoro-A -pregnene-16a,l7u-diol-3,Z0-dione 16,17-acetonide 3-ethylene ketal is obtained.

6 EXAMPLE 8 6-Brom0-A -Pregnene-16a,] 7a-Di0l-3,20-Di0ne 16,1 7-A cetonide 3-Ethylene Ketal Following the procedure of Example 1, but substituting 6B-bromo-16a, l7 a-dihydroxyprogesterone 16,17-acetonide for the l7u-dihydroxyprogesterone 16,17-acetonide, 6-bromo-A -pregnene-l6a,17a-dio1-3,20-dione 16,17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 9 6-Fluoro-A -Pregnene-l 6a,] 7 a-Diol-3,20-Dione 16,17-Acet0phen0nide 3-Ethylene Ketal Following the procedure of Example 1, but substituting 6a-fluoro-16u,17a-dihydroxyprogesterone 16,17 acetophenonide for the 16a,17ot-dihydroxyprogesterone 16,17- acetonide, 6 fiuor0-A -pregnene-16a,l7a-diol-3,20-dione 16, 17-acetophenonide 3-ethylene ketal is obtained.

EXAMPLE 10 6 -F luoro-M-Pregnene-I 6 0:,1 7u-Diol-3,20-Dione 16,17-Acetophenonide S-Ethylene Ketal EXAMPLE 11 6-Methyl-16a,1 7otDihydr0xypr0gester0ne 160a,] 7 a- Acetonide 3-Ethylene Ketal Following the procedure of Example 1, but substituting an equivalent amount of 6ot-methyl-16a,17tx-dihydroxyprogesterone 16,17-acetonide for the l6a,17a-dihydroxyprogesterone 16,17-acetonide, G-methyl-l6u,17u-dihydroxyprogesterone 16a,17a-acetonide 3-ethylene ketal is obtained.

EXAMPLE 12 6-Methyl-1 6 a,1 7 ut-Dihydroxyprogesterone 1 6 (1,1 7 a- Acetonide S-Ethylene Ketal Following the procedure of Example 1 but substituting an equivalent amount of fl-rnethyl-l6a,17a-dihydr0xyprogesterone 16,17-acetonide for the 16a,l7u-dihydroxyprogesterone 16,17-acetonide, 6-methylA -pregnene-l6a, t-diO1-3,20-di0116 16,17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 13 6-Methyl-M-Pregnene-16a,] 7ot-Di0l-3,20-Di0ne 16,1 7- Acetophenonide 3-Elhylene Ketal Following the procedure of Example 1 but substituting an equivalent amount of 6a-methyl16a,l7a-dihydroxyprogesterone 16,17-acetophenonide for the l6ot,17a-dihy droxyprogesterone 16,17-acetonide, 6-methyl-A -pregnene- 16cc,17oc-di0l3,20-di0fl6 16,17-acetophenonide 3-ethy1ene ketal is obtained.

EXAMPLE 14 A solution of 100 mg. of l6m,17u-dihydroxyprogesterone 16,17-acetonide 3-monoethylene ketal and 100 mg. of lithium aluminum hydride in 15 ml. of anhydrous ether is refluxed for 2 hours and then stirred at room temperature for 18 hours. Saturated sodium sulfate solution is slowly added until a precipitate begins to form whereupon the ether layer is decanted and the precipitate washed several times with additional amounts of ether. After evaporation of the ether in vacuo the crude residue (about 92 mg.) is crystallized from acetone-hexane yielding about 74 mg. of 3-ethylenedioxy-16a,17a-isopropylidenedioxy- A -pregnene-2O B-ol, M.P. about 175l77 C.

Recrystallization from acetone-hexane gives the analytically pure ketal with the following properties: M.P. about 175l77 C.; -27.5 (c., 1.1 in chlf.);

max.

no selective U.V. absorption.

Anal.-Calcd. for C H O (432): C, 72.19; H, 9.32. Found: C, 72.42; H, 9.42.

The reduction of 16a,17a-dihydroxyprogesterone 16a, 17a-acetonide 3-mono-ethylene ketal can also be accomplished with sodium borohydride in isopropanol or with lithium borohydride in dry ether as illustrated by the fo1- lowing examples:

EXAMPLE 15 To a solution of 25 mg. of 16a,17ot-dihydroxyprogesterone 16a,17 x-acetonide 3-monoethylene ketal in 10 ml. of isopropanol is added 100 mg. of sodium borohydride and the resulting mixture is refluxed for 18 hours. After cooling, aqueous methanol is added to destroy the excess borohydride and the reaction mixture is concentrated in vacuo to remove most of the alcohol. Dilution with water produces a precipitate which is filtered, washed Well with water and dried in vacuo. An infrared spectrum of this material proved it to be identical with the ZO/i-hydroxy compound obtained in Example 14.

EXAMPLE 16 A solution of 25 mg. of 16a,17a-dihydroxyprogesterone 16a,17a-acetonide 3-monoethylene ketal and 50 mg. of lithium borohydride in 10 ml. of dry ether is stirred at room temperature for 18 hours. Water is added to destroy the excess borohydride and the ether is removed in vacuo. Crystalline material separates, which is filtered, washed well with water and dried in vacuo. An infrared spectrum of the dried material is identical with that obtained in Example 14.

EXAMPLE 17 3 -Elhylenedixy-1 6a,] 7 06- a-Phenyl-fi-M ethyl -M ethylenedioxy-M-Pregnene-Z 0,8-0l

A solution of 25 mg. of 16a,17u-dihydroxyprogesterone 16,17-acetophenonide 3-ethylene ketal in 10 ml. of isopropanol is refluxed for 18 hours. Aqueous methanol is added to the cooled reaction mixture to destroy the excess borohydride and the alcohol is then removed by evaporation in vacuo. Dilution with more water gives a crystalline precipitate, which is filtered, washed Well with water and dried in vacuo. An infrared spectrum of the precipitate indicates complete reduction of the ZO-ketone. Crystallization from acetone-hexane gives the analytically pure derivative of A -pregnene-16a,17a,20fi-triol-3-one 16,17-acetophenonide 3-ethylene ketal (ix-phenyl isomer) with the following properties: M.P. about 221-223 C.;

[@ 37 (c., .9 in chlf.);

my 2.79, 13.11 and 14.26..

no selective U.V. absorption.

AnaI.Calcd. for C H O (494): C. 75.27; H, 8.56. Found: C, 75.03; H, 8.60.

The same product is obtained when the reaction is conducted at room temperature for 18 hours. 16:1,17tx-dihydroxyprogesterone 16a,17-acetophenonide 3-ethylene ketal is also completely reduced by lithium borohydride in dry ether at room temperature for 18 hours.

O 0 EXAMPLE 18 16,17-C/zl0ral Derivative of A -Pregnene-16aJ 711,205-

T ri0l-3-0ne S-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of the 16a,17ot-Ch10l2ll derivative of A -pregnene-16a,17a-diol-3,20dione 3-ethy1ene ketal for the 16a,17ot-dihydroxyprogesterone 16,17-acetonide 3- ethylene ketal, the 16,17-cl1loral derivative of A -pregmeme-16a,l7ot,20p-triol-3-one 3-ethylene ketal is obtained.

EXAMPLE 19 16,17-Dicycl0pr0pyl Ketone Derivative 0 A -Pregnene- 16a,17ot,20fl-Tri0l-30He S-Ethylene Kelal Following the procedure of Example 14 but substituting an equivalent amount of the 16,17-dicyclopropyl ketone derivative of 16a,17u-dihydroxyprogesterone 3-ethylene ketal for the 16a,17a-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal, the 16,17-dicyclopropyl ketone derivative of A -pregnene-16a,l7a,2Op-triol-3-one 3-ethylene ketal is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetone derivative, the heptafluorobutanal derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaldehyde derivative, the furfural derivative, the benzophenone derivative and the 2-acetylfuran derivative of 16a,17a-dihydroxyprogesterone 3-ethylene ketal, yield the methylisobutyl ketone, the cyclopropylphenyl ketone, the cyclohexyl methyl ketone, the 1,1,l-trifiuoroacetonide, the heptafluorobutanal, the p-chloroacetophenone, the pnitroacetophenone, the benzaldehyde, the furfural, the benzophenone and the 2-acety1furan derivatives of A pregnene-16a,17a,20[i-triol-3,20-dione 3-ethylene ketal, respectively.

EXAMPLE 20 6-Chl0r0-A -Pregnene-16a,] 7a,20,B-Tri0l-3-0ne 16,17- Acetonide 3-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6fl-chloro-16e,17a-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal for the 16a,17a-dihydroxyprogesterone 16,17-acetonidc 3-ethylene ketal, 6-chlor0-A -pregnene-16a,17a,20[3-triol-3-one 16,17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 21 6-Flu0r0-A -Pregnene-l 6a,] 7a,20fl-Tri0l-3-0ne 16,17-

A cetonide 3 Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6-fiuoro-16a,17a-dihydroxyprogesterone 16,17-acetonide S-ethylene ketal for the 16a,17e-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal, 6-fluoro-A -pregnene-16a,17e,20fl-triol-3-or1e 16,17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 22 6-Br0m0-A -Pregnene-16a,] 7a,20B-Tri0l-3-0ne 16,1 7- Acetonide 3-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6-bromo-16e,17a-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal for the 16a, 17a dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal, 6-bromo-A -pregnene-16a,17a,205-triol-3-one 16, 17-acetonide 3-ethylene ketal is obtained.

EXAMPLE 23 fi-Fluoro-A -Pregnene-16a,17u,20,8-Tri0l-3-One 16,17- Acetophenonide 3-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6-fluoro-16a,17ot-dihydroxyprogesterone 16,17-acetophenonide 3-ethylene ketal for the 16a,17a-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal, 6 -fluoro-A -pregnene-16oc,17a,2Ofl-triol-3 one 16,17-acetophennide 3-ethylene ketal is obtained.

Similarly, the 3-ethylene ketals of 16a,171x-(2'-butylidene) 1611,17a-dihydroxy-fi-fluoroprogesterone, 1605,17!!- (4 methyl-2'-pentylidene) 160C,170L-dihYdI'OXY-6-Chl0l'0- progesterone, 166t,17a-cyclohexylidene 16a,17a-dihydroxy- 6-fluoroprogesterone and l6ot,l7a(3-pentylidene) 16a, 17a-dihydroxy-6-fluoroprogesterone yield their respective 20/8-hydroxy derivatives.

EXAMPLE 24 6-Methyl-A -Pregnene-16a,17a,20,B-Tri0l-3-One 16,17- Acetolzide S-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6-methyl-16a,17a-dihydroxyprogesterone 16,17-acetonide 3-ethylene ketal for the 16cc, 17cc -dihydroxyprogesterone 16,17-acetonide 3-ethylene I ketal, 6-methyl-A -pregnene-l61x,l7a,2O/3-triol-3-one l6,

l7-acetonide 3-ethy1ene ketal is obtained,

EXAMPLE 25 6-Methyl-A -Pregnene-16a,71 6t,20fi-Tri0l-3-One 16,1 7- Acetophenonide 3-Ethylene Ketal Following the procedure of Example 14 but substituting an equivalent amount of 6-methyl-16a,17a-dihydroxyprogesterone 16,17-acetophenonide 3-ethylene ketal for the 16a,l7ot dihydroxyprogesterone 16,17-acetonide 3-ethy1- ene ketal, 6-methyl-A -pregnene-16a,17,2Ofl-t1'i0l-3-0ne 16,17-acetophenonide 3-ethylene ketal is obtained.

EXAMPLE 26 A -Pregnene-16a,17a,20,8-Triol-3-0ne .1 6 11,1 7u-A cetonide mm 2.95 6.00 and 6.19 1; mg, 240 my (e=19,000)

Anal.Calcd. for C I-1 0 (388): C, 74.19; H, 9.34. Found: C, 74.44; H, 9.26.

EXAMPLE 27 A solution of 90 mg. of A -pregnene-l6a,17ot,2O18-triol- 3-one l6u,l7u-acetophenonide 3-ethylene ketal in ml. of methanol and 0.68 ml. of 8% (w./v.) of sulfuric acid is refluxed for 30 minutes. The acid is neutralized by the addition of bicarbonate solution and most of the methanol is evaporated in vacuo. Dilution with water yields a crystalline precipitate which is filtered, washed and dried in vacuo. This material possesses an ultraviolet spectrum indicating complete hydrolysis.

A mo mp $15,750

Crystallization from 95% ethanol gives the analytically pure A -pregnene-16m,17a,2O/3-triol-3-one 16u,l7u-acetophenonide (ct-phenyl isomer) possessing the following physical properties: M.P. about 193-195 [121 +17 (c., 0.9 in chlf.)

71 2 ,210 m, (e=15,750); 123? 2.96, 6.05, 6.20, 12.92, 13.02 and 14.16,.

Anal.Calcd. for C H O (450): C, 77.30; H, 8.50. Found: C, 77.45; H, 8.57.

10 EXAMPLE 2s 16,17-Chl0ral Derivative of A -Pregnene-16u,17a,20fl- Triol-3-One Following the procedure of Example '26, but substituting an equivalent amount of the 16,17-chlora1 derivative of M-pregnene-l6a,l7a,20fi-triol-3-one 3-ethylene ketal for the 3-ethylenedioxy-l6ct,l7a-isopropylidenedioxy-A pregnene-ZOB-ol, the 16,17-chloral derivative of A -pregnene-16a,17a,20fl-triol-3-one is obtained.

EXAMPLE 29 16,17-Dicycl0pr0pyl Ketone Derivative of A -Pregnenea,] 7a,20,B-Triol-3-One Following the procedure of Example 26, but substituting an equivalent amount of the 16,17-dicyclopropyl ketone derivative of A -pregnene-16u,17u,Q0,B-triol-3-one 3-ethylene ketal for the 3-ethylenedioxy-16ot,l7u-isopropylidenedioxy-A -pregnene-20fl-ol, the 16,17-dicyclopropyl ketone derivative of A -pregnene-l6a,17a,20;8-triol-3- one is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,l-trifluoroacetone derivative, the heptafluorobutanal derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaldehyde derivative, the furfural derivative, the benzophenone derivative and the 2-acetylfuran derivative of A pregnene-l6ot,l7ot,20[3-trio1-3-one 3-ethylene ketal, yield the methylisobutyl ketone, the cyclopropyl phenyl ketone, the cyclohexyl methyl ketone, the 1,1,1-trifluoroacetonide, the heptafluorobutanal, the p-chloroacetophenone, the pnitroacetophenone, the benzaldehyde, the furfural, the benzophenone and the 2-acetyl furan derivatives of A pregnene-l6u,17u,20fl-triol-3-one, respectively.

EXAMPLE 30 6 u-chloro-A -Pregnene-l 6 u,] 7a,20p-Tri0l-3-0ne 16,1 7 -A cetonide Following the procedure of Example 26, but substituting an equivalent amount of 6-chloro-A -pregnene-16a, l7a,20fl-triol-3-one 16,17-acetonide 3-ethylene ketal for the 3-ethylenedioxy-16a,17a-isopropylidenedioXy-A -pregnene 205-01, 6a-chloro-A -pregnene-l6a,17,2OB-tti0l-3- one 16,17-acetonide is obtained.

EXAMPLE 31 6ot-Flu0r0-A -Pregnene-16ot,1 7a,20/3-Tri0l-3-One 16,17-Acet0nide Following the procedure of Example 26, but substituting an equivalent amount of 6-fluoro-A -pregnene-16a, 17a,20fl-triol-3-one 16,17-acetonide 3-ethylene ketal for the 3-ethylenedioxy-16a,17u-isopropylidenedioxy-A -pregnene 205 01, 60a 7 fluoro A pregnene 16a,170t,20fl triol-3-one 16,17-acetonide is obtained.

EXAMPLE 32 Following the procedure of Example 26, but substituting an equivalent amount of 6-bromo-A -pregnene-16a, :,20/3-l1i0l-3-0I16 16,17-acetonide S-ethylene'ketal for the 3 ethylenedioxy 166t,170t isopropylidenedioxy- A pregnene 205 01, 6oz bromo A pregnene 16a, 17a,20B-1l1l0l-3-0I16 16,17-acetonide is obtained.

EXAMPLE 33 6 OL-F l acre-A4 -Pregnene-1 6 0a,] 7u,20,B-Tri0l-3-One 16,.1 7-A cetophenonide Following the procedure of Example 26, but substituting an equivalent amount of 6-fluoro-A -pregnene-l6u, 17a,20,8-triol-3-one 16,17-acetophenonide 3-ethylene ketal for the 3-ethylenedioxy-16a,17a-isopropylidenedioxy-A pregnene 20B 01, 60c fiuoro A pregnene l6ot,l7ot, 20,8-triol-3-one 16,17-acetophenonide is obtained.

EXAMPLE 34 6a-Methyl-A -Pregnene-16ecJ 7a,20B-Triol-3-One 16,17-Acetnide Following the procedure of Example 26, but substituting an equivalent amount of 6-methyl-A -pregnene-16u, 17a,20fi-triol-3-one 16,17-acetonide 3-ethylene ketal for the 3 ethylenedioxy 16a,17 x isopropylidenedioxy- A -pregnene-2Ofl-ol, 6u-methyl-A -pregnene-16a,17u, 20;3- triol-3-one 16,17-acetonide is obtained.

EXAMPLE 35 6a-Methyl-A -Pregnene-1 6 ,1 7 u,2 Ofi-Tri0l-3-One 16,1 7-A cetophenonide Following the procedure of Example 26 but substituting an equivalent amount of 6-methyl-A -pregnene-l6ot, 17a,20/3-triol-3-one 16,17-acetophenonide 3-ethylene ketal for the 3-ethylenedioxy-16a,17tx-isopropylidenedioxy-A pregnene 205 01, 6a fluoro A pregnene 16u,17a, 20fl-triol-3-one 16,17-acetophenonide is obtained.

EXAMPLE 36 80 mg. of A -pregnene-16a,17u,20fl-triol-3-one l6ot,17aacetonide is dissolved in 5 ml. of dry pyridine and 2.5 ml. of acetic anhydride and the mixture is allowed to stand at room temperature for 18 hours. Ice is then added to the reaction mixture and the resulting precipitate is filtered, washed well with water and dried in vacuo. Crystallization from acetonehexane yields the pure ZOE-acetate with the following properties: M.P. about 243-245"; +104 (c., 0.8 in chlf.)

W 5.73, 5.94, 6.17 and 8.00,. aM 140 Similarly, if other acylating agents are substituted for the acetic anhydride in the above procedure, the corresponding 20-esters are formed. Thus, propionic anhydride yields the 20fi-propionate and benzoyl chloride yields the 20,8-benzoate. Moreover, if other acetals and ketals are substituted for the A-pregnene-l6u,l7ot,20fitriol-3-one 16,17-acetonide in the above procedure, the corresponding ZOB-acetates are obtained.

The following examples illustrate the preparation of the final compounds of this invention by the second alternative method. In these examples l6u,17a-dihydroxyprogesterone 16,17-acetophenonide is employed as the starting steroid. The method is, however, equally applicable for converting any of the starting steroids of this invention to their respective final products.

EXAMPLE 37 A solution of 50 mg. of 16a,17a-dihydroxyprogesterone 16,17-acetophenonide (a-phenyl isomer) and 100 mg. of lithium aluminum hydride in 5 ml. of freshly distilled tetrahydrofuran is refluxed for 19 hours. The reaction is stopped by the addition of saturated sodium sulfate solution, filtered by gravity and the precipitate washed thoroughly with ether. Evaporation of the ether-tetrahydrofuran solution gives about 55 mg. of a crude residue which after two crystallizations from methanol gives pure 319, ZOfl-diol having the following properties: M.P. about 174- 175; 7.8 (c., .69 in chlf.).

EXAMPLE 38 1 6 0a,] 7aa-Phenyl-p-M ethyl M ethylenedioxy-M- Pregnene-20fl-0l-3-One To a solution of 12 mg. of 16u,17a-(ot-phenyl-,8-

methyl)methylenedioxy-A -pregnene-35,20f3-diol in 2 ml. of chloroform is added 120 mg. of active manganese dioxide prepared according to Attenburrow, et al., J. Chem. Soc., 1094 (1952). The suspension is shaken at room temperature for 48 hours, filtered and the manganese dioxide washed thoroughly with chloroform. Evaporation of the chloroform solution to dryness afforded pure product melting at about 187-188, identical in all respects with the compound prepared in Example 34.

EXAMPLE 39 16a,] 7 0t- Ot-M ethy I-B-Phenyl) M ethylenedioxy-M- Pregnene-3B,20fi-Diol Fifty milligrams of 16a,17a-dihydroxyprogesterone acetophenonide (fi-penyl isomer) is reduced with lithium aluminum hydride in tetrahydrofuran as described in Example 37 for the ot-phenyl isomer. The resulting amorphous 35,20B-diol is used in Example 40 without further purification.

EXAMPLE 40 1 6 (1,1 70t- (Ct-M ethyl-B-Phenyl M ethyl enedioxy-M- Pregnene20,B-Ol-3-One The crude 3fag20B-diol obtained in Example 39 is oxidized with active manganese dioxide as follows: To a solution of 53.5 mg. of the crude steroid in 2.5 ml. of chloroform is added 500 mg. of manganese dioxide and the mixture shaken for 48 hours at room temperature. The mixture is filtered, and the precipitate washed thoroughly with hot chloroform. The chloroform solution on evaporation in vacuo furnishes about 36 mg. of (a methyl B phenyl)methylenedioxy A pregnene-20,8-ol-3-one, which on recrystallization from methanol furnishes analytically pure material possessing the following properties: M.P. about 290-291"; [07] f+67 (0., 1.0 in chlf.)

Analysis.Calcd. for C H O (450.59); C, 77.30; H, 8.50. Found: C, 77.56; H, 8.43.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

l. A compound of the formula wherein R is selected from the group consisting of nydrogen, chlorine, fluorine and lower alkyl; R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon caroxylic acid of less than ten carbon atoms; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cyeloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloakyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocyclic.

2. A -pregnene-16a,l7a,20p3-triol-3-one 16,17-acetonide.

3. A--pregnene-l6ot,l7ot,20B-triol-3-one 16,17-acetophenonide.

13 4. 6-chloro-A -pregnene-l6m,l7ct,20,B-triol-3-one 16-17- acetonide.

5. 6-methyl-M-pregnene-16oz,l7a,20fl-triol-3-one 16,17- acetonide.

6. A compound of the formula wherein R is selected from the group consisting of hydrogen, chlorine, fluorine and lower alkyl; A is lower alkylene; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, moncyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heteroyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocyclic.

7. 3-ethylenedioxy l6a,17ot isopropylidenedioxy A pregnene-ZO-one.

8. 3-ethylenedioxy l6a,l7a (a-phenylethylenedioxy)- A -pregnene-20-one.

9. A compound of the formula i HO-C-H rib wherein R is selected from the group consisting of hydrogen, chlorine, fluorine and lower alkyl; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocyclic.

13. 16a,l7a-isopropylidenedioxy-M-pregnene 313,201.; diol.

14. 16a,17w(a-phenylethylenedioxy)-A -pregnene 3,8, ZOfi-diol.

References Cited in the file of this patent UNITED STATES PATENTS 2,911,403 Sondheimer et al. Nov. 3, 1959 2,931,806 Sarett Apr. 5, 1960 2,932,638 Gould et al. Apr. 12, 1960 OTHER REFERENCES Fieser et al.: Steroids, Rheinhold Publishing Corp., June 25, 1959, page 563.

Mazur et al.: Tetrahedron, 1959, vol. 7, pages l30137.

Zander et al.: The Journal of Clinical Endrocrinology and Metabolism, vol. XVHI, No. 4, April 1958, pages 337-353.

Fried et al. (I): Chemistry and Industry, Apr. 15, 1961, pages 465-466.

Fried et a1. (II): Chemistry and Industry, Apr. 15, 1961, pages 466-468.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 134,770 May 26, 1964 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 47, for "posses" read possess column 5, line 12, for "Choral", in italics, read Chloral in italics; lines 30 and 31, for "l7a-diol 3-ethylene ketal" read l7 -diol-3,20-dione Iii-ethylene ketal same column 5, lines 34 and 35, after "derivativefl, insert the column 9, line 22, for "716,", in italics, read 17 in italics; column 10, line 69, for "A b, in italics, read A in italics; column 11, line 43, for "QA read A column 12, line 13, for "([3- penyl isomer)" read ([S-phenyl isomer) line 60, for "caroxylic" read carboxylic column 13,

lines 6 to 17, the upper right-hand portion of the formula should appear as shown below instead of as in the patent:

Signed and sealed this 30th day of March 1965,

(SEAL) .p. Attest:

ERNEST W. SWIDER EDWARD J, BRENNER A'ttesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA 